US9078925B2 - Pharmaceutical semi-solid composition of isotretinoin - Google Patents

Pharmaceutical semi-solid composition of isotretinoin Download PDF

Info

Publication number
US9078925B2
US9078925B2 US14/133,073 US201314133073A US9078925B2 US 9078925 B2 US9078925 B2 US 9078925B2 US 201314133073 A US201314133073 A US 201314133073A US 9078925 B2 US9078925 B2 US 9078925B2
Authority
US
United States
Prior art keywords
isotretinoin
pharmaceutical composition
oral pharmaceutical
dissolution
formulation
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
US14/133,073
Other languages
English (en)
Other versions
US20140107203A1 (en
Inventor
Arthur M. Deboeck
Francis Vanderbist
Cecile Servais
Philippe Baudier
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
GALEPHAR PHARMACEUTICAL RESEARCH Inc
Original Assignee
GALEPHAR PHARMACEUTICAL RESEARCH Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
US case filed in New Jersey District Court litigation Critical https://portal.unifiedpatents.com/litigation/New%20Jersey%20District%20Court/case/2%3A19-cv-02546 Source: District Court Jurisdiction: New Jersey District Court "Unified Patents Litigation Data" by Unified Patents is licensed under a Creative Commons Attribution 4.0 International License.
First worldwide family litigation filed litigation https://patents.darts-ip.com/?family=50475895&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=US9078925(B2) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority claimed from US13/525,857 external-priority patent/US8952064B2/en
Priority to US14/133,073 priority Critical patent/US9078925B2/en
Application filed by GALEPHAR PHARMACEUTICAL RESEARCH Inc filed Critical GALEPHAR PHARMACEUTICAL RESEARCH Inc
Publication of US20140107203A1 publication Critical patent/US20140107203A1/en
Priority to EP14872811.6A priority patent/EP2964195A4/fr
Priority to PCT/US2014/066756 priority patent/WO2015094574A1/fr
Assigned to GALEPHAR PHARMACEUTICAL RESEARCH, INC. reassignment GALEPHAR PHARMACEUTICAL RESEARCH, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: DEBOECK, ARTHUR, VANDERBIST, FRANCIS, BAUDIER, PHILIPPE, SERVAIS, CECILE
Publication of US9078925B2 publication Critical patent/US9078925B2/en
Application granted granted Critical
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/203—Retinoic acids ; Salts thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4875—Compounds of unknown constitution, e.g. material from plants or animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers

Definitions

  • the present invention relates to an oral pharmaceutical composition of isotretinoin containing at least two excipients, one of them being hydrophilic (i.e. having an HLB value superior or equal to 10), and the other being an oily vehicle.
  • Isotretinoin 13-cis retinoic acid or 13-cis vitamin A
  • isomers and some of its analogs are widely known to have therapeutic activity in the treatment of several severe skin disorders including cystic acne, hypertrophic lupus erythematosus, and keratinization disorders.
  • cystic acne cystic acne
  • hypertrophic lupus erythematosus hypertrophic lupus erythematosus
  • keratinization disorders Some evidence exists supporting the activity of isotretinoin in basal cell carcinoma and squamous cell carcinoma.
  • isotretinoin is also a highly toxic drug. Indeed, although isotretinoin, which is a cis derivative, is known to be less toxic than all trans vitamin A derivatives, side effects resulting from its use such as headache, vomiting, irritation of mucosa and liver toxicity, occur frequently. Furthermore, isotretinoin is known to be highly teratogenic in both animals and humans.
  • Isotretinoin is a reddish-orange powder that is decomposed in the presence of light and atmospheric oxygen. Isotretinoin is poorly soluble in water, which results in its bioavailability being quite low after an oral intake (25% in fasted conditions and 40% in fed conditions).
  • the maximum concentration (C max ) is reached after 24 hours, while the (C max ) of the active metabolite, 4-oxo-isotretinoin is reached after 6 hours.
  • the elimination half-life of isotretinoin is of 7 to 37 hours while the half-life (t 1/2 ) of the active metabolite is of 11 to 50 hours.
  • the steady-state concentrations of isotretinoin are reached after 1 week of treatment.
  • compositions of isotretinoin involve the use of an antioxidant agent and of a carrier like lactose, starches or polyethylene glycols.
  • EP 0184942 describes more specific compositions of isotretinoin involving the use of an antioxidant, a chelating agent, a pharmaceutical carrier and a suspending agent. The composition obtained is described as being stable over time.
  • U.S. Pat. No. 4,545,977 relates to improved compositions of isotretinoin wherein taurine is associated with isotretinoin to reduce the drug's side effects.
  • U.S. Pat. No. 5,716,928 describes a method for increasing bioavailability and for reducing inter and intra individual variability of an orally administered hydrophobic pharmaceutical compound.
  • the method includes orally administering the pharmaceutical compound with an essential oil or essential oil component in an amount sufficient to provide greater bioavailability of the active ingredient.
  • U.S. Pat. No. 6,028,054 relates to a method for increasing bioavailability of an orally administered hydrophobic pharmaceutical compound to humans.
  • the method includes orally administering the pharmaceutical compound concurrently with a bioenhancer comprising an inhibitor of an cytochrome P450 3A enzyme or an inhibitor of P-glycoprotein mediated membrane transport.
  • U.S. Pat. No. 5,993,858 describes a self-microemulsifying excipient formulation for increasing the bioavailability of a drug which includes an emulsion including an oil or other lipid material, a surfactant and an hydrophilic co-surfactant.
  • compositions of isotretinoin containing at least two lipid materials, one of them being hydrophilic may be a suspension, emulsion or microemulsion.
  • Isotretinoin is characterized by a low absolute bioavailability and a high inter and intra individual variability. Isotretinoin also presents a wide range of side effects among which some are severe (e.g., ocular, skin anemia, hepatic). It is consequently of particular interest to provide a reliable, stable and highly bioavailable formulation of isotretinoin.
  • the present invention is related to a pharmaceutical composition comprising isotretinoin which does not exhibit significant food effect as determined in vivo by pharmacokinetic studies and in vitro by dissolution in 900 mL of pH 7.5 Buffer containing 0.11% of pancreatin, 4.7% cholic acid, 0.14% sodium dihydrogen phosphate, and 0.5% sodium hydroxide using a USP Apparatus #2 (paddles), at 100 rpm and 37° C.
  • the term “food effect” is defined as a significant difference in maximum concentration, as determined by Area Under the Curve, when an oral drug product is taken with or without food.
  • a semi-solid dosage form containing isotretinoin is a form in which isotretinoin is mixed with suitable melted excipients. The molten mix is then filled, for example, into hard gelatin capsules or other pharmaceutically acceptable capsules. At ambient temperature (temperature for example of less than 20° C.), the content of the capsule is a solid while at a temperature higher than 20° C.
  • the isotretinoin may be solubilized in the mix of excipients or partially solubilized.
  • the active ingredient may also be formulated as a suspension, emulsion or microemulsion.
  • lipidic excipients are available to the formulator to obtain a semi-solid formulation.
  • Excipients compatible with hard gelatin capsule shells are: lipophilic liquid vehicles (refined specialty oils, medium-chain triglycerides and related esters), semi-solid lipophilic vehicles, solubilizing agents, emulsifying agents and absorption enhancers.
  • the classification of fatty excipients is based on the hydrophilicity or lipophilicity of the excipients, characterized by the hydrophilic/lipophilic balance value (HLB).
  • HLB hydrophilic/lipophilic balance value
  • lipophilic excipients are vegetable oils (e.g., peanut oil, olive oil, soyabean oil, etc.) fatty acids (e.g., stearic acid, palmitic acid, etc.) fatty alcohols, etc.
  • hydrophilic excipients are polyethylene glycol (PEG) with a molecular weight of greater than 3,000.
  • PEG polyethylene glycol
  • amphiphilic (i.e., having lipophilic and hydrophilic properties) excipients are Poloxamers, Lecithin, PEG esters (Gelucire®), etc.
  • the choice of the nature of the formulation influences the stability of the pharmaceutical formulation and the bioavailability of the isotretinoin contained in it.
  • a maximum bioavailability is achieved by preparing and keeping the drug in the amorphous/solubilized state in a solid dispersion or in a lipid-based formulation.
  • the obstacle to dissolution that we are avoiding is significant “washing out” of the compound from solution into an insoluble crystalline form during the dissolution/release step in vivo.
  • These systems may consist of suspension, emulsion, microemulsion, self-emulsifying drug delivery systems (SEDDS®) or self-emulsifying microemulsion drug delivery system (SMEDDS®).
  • SEDDS® self-emulsifying drug delivery systems
  • SMEDDS® self-emulsifying microemulsion drug delivery system
  • Microemulsions have the added advantage over suspensions, such as emulsions and dispersions, since thermodynamically they are more stable, they can be manufactured with little energy input and have generally a longer shelf-life. Nevertheless, a microemulsion formulation is not a guarantee of higher bioavailability in comparison to a suspension, as described hereafter.
  • oil-in-water (O/W) and water-in-oil (W/O) micro emulsions usually involves a combination of 3-5 basic compounds i.e. oil, surfactant, co-surfactant, water and electrolytes.
  • the challenge is to select, for a particular application, oil(s) and surfactant(s) that are acceptable from a toxicological perspective and that provide a high bioavailability of the drug, i.e. isotretinoin.
  • FIG. 1 is a ternary diagram of a formulation containing only Gelucire® 50/13 and soybean oil, the third component being water.
  • FIG. 2 shows the dissolution rate of a reference product (Roaccutane®-20 mg active agent), of a suspension containing 20 mg isotretinoin and of an emulsion SEDDS® containing 10 mg isotretinoin.
  • FIG. 3 shows an in vivo comparative pharmacokinetic profile of isotretinoin.
  • FIG. 4 shows comparative pharmacokinetic profiles of isotretinoin.
  • FIG. 5 shows comparative pharmacokinetic profiles of different formulations for 4-oxo-isotretinoin, the active metabolite of isotretinoin.
  • FIGS. 6 and 7 illustrate the mean pharmacokinetic profiles of isotretinoin and 4-oxo-isotretinoin for two formulations.
  • FIG. 8 shows in vivo comparative pharmacokinetic profiles of isotretinoin obtained after administration of 2 ⁇ 20 mg of the present invention versus 20 mg of a product in the market (Accutane®) taken with and without food.
  • the pharmaceutical composition of the invention is an oral semi-solid pharmaceutical composition of isotretinoin containing two lipidic excipients, one of them being hydrophilic and the other being an oily vehicle.
  • the hydrophilic excipient has a HLB value of at least 10, for example equal to 10, but preferably greater than 10, such as greater or equal to 12, for example between 12 and 14.
  • the pharmaceutical composition of the invention contains advantageously at least one hydrophilic excipient with a HLB value of at least 10 selected from the group consisting of glyceroyl macrogolglycerides, polyethyleneglycol derivatives, and mixtures thereof.
  • the pharmaceutical composition contains from 20 to 80% by weight of a hydrophilic excipient with a HLB value of at least 10 selected from the group consisting of glyceroyl macrogolglycerides, polyethyleneglycol derivatives, and mixtures thereof.
  • the oily vehicle is selected from the group consisting of vegetable oils, medium chain triglycerides, fatty acid esters, amphiphilic oil, glycerol oleate derivative, and mixtures thereof.
  • the composition may contain from 5 to 70% by weight of an oily vehicle selected from the group consisting of vegetable oils, medium chain triglycerides, fatty acid esters, amphiphilic oil, glycerol oleate derivative, and mixtures thereof.
  • the composition further contains at least one surfactant, preferably selected from the group consisting of sorbitan fatty acid esters, polysorbate derivatives, polyoxyethylene sorbitan fatty acid esters, sodium laurylsulphate, derivatives of lecithine, propylene glycol esters, fatty acid esters of propylene glycol, fatty acid esters of glycerol, polyethylene glycol, and mixtures thereof.
  • the composition contains from 1 to 10% by weight of at least one surfactant.
  • the pharmaceutical formulation of the invention contains advantageously at least one disintegrant, preferably selected from the group consisting of povidone derivative, sodium croscarmellose and mixtures thereof.
  • the pharmaceutical composition of the invention may contain one or more surfactants and/or one or more disintegrants, but contains preferably one or more compounds acting as surfactants and one or more compounds acting as disintegrants.
  • the invention relates also to a pharmaceutical acceptable capsule containing at least one semi-solid composition of the invention, for example at least one composition of the invention as disclosed above.
  • the capsule is for example selected from the group consisting of hard gelatin capsules, soft gelatin capsules, hypromellose capsules, and starch capsules.
  • the invention also relates to an oral pharmaceutical composition
  • an oral pharmaceutical composition comprising isotretinoin, wherein said oral pharmaceutical composition is substantially devoid of food effect as characterized by a dissolution profile wherein at least 70% of the oral pharmaceutical composition is dissolved after about four hours in a USP2 dissolution apparatus at a paddle speed of 100 rpm, and a dissolution media composed of 900 mL of pH 7.5 buffer containing 0.11% pancreatin, 4.7% cholic acid, 0.14% sodium dihydroxide phosphate and 0.5% sodium hydroxide at 37° C.
  • the dissolution test method of the present invention is carried out in 900 mL of pH 7.5 Buffer containing 0.11% of pancreatin, 4.7% cholic acid, 0.14% sodium dihydrogen phosphate, and 0.5% sodium hydroxide using USP Apparatus #2 (paddles), at 100 rpm and 37° C. Dissolution samples are taken after 4 hours, and diluted to 50% with acetonitrile. Any USP-acceptable dissolution equipment may be used.
  • a USP dissolution apparatus #2 or #3 is used. More preferably, a USP #2 (paddle) dissolution apparatus equipped with 900 mL round bottomed and/or peak vessel flasks is used.
  • sinkers can be used with any dosage form that floats in the dissolution media.
  • a small, non-reactive wire helix may be attached to the dosage form to keep it at the bottom of the vessel.
  • Preferred sinkers include the Sotax® sinker, basket sinker, pronger sinker, O-ring, or spiral sinker. More preferred sinkers include the Japanese Pharmacopeia basket sinkers.
  • the pH of the media may vary from 2.0 to 12.0, preferably from 4.0 to 8.0, and more preferably from 7.0 to 8.0.
  • the buffer of the media may be comprised of phthalate, phosphate, barate, and/or acetate, and will depend on the final pH value. Sodium dihydrogen phosphate is the preferred buffer. Pancreatin is added to the media to destroy any gelatin cross-linking.
  • Cholic acid is added to increase the solubilization of isotretinoin.
  • the amount may vary from 0.1% to 0.6%, preferably from 0.3% to 0.4%.
  • any validated analytical method may be used, including UV spectrophotometry, colorimetry, HPLC, or capillary electrophorese.
  • the preferred analytical method is HPLC equipped with a UV detector of 353 mm and C 18 column, for example, LiCrospher® 100 RP-18 end capped, with a flow rate of 2.0 mL/min of mobile phase consisting of acetonitrile:water:glacial acetic acid (85:15:0.5) at a temperature of 40° C.
  • the present invention relates to a semi-solid formulation of isotretinoin containing at least 2 lipidic excipients, one of them being a hydrophilic excipient (having a high HLB value, namely >10) and the other an oily excipient.
  • the molten mix of these two excipients allows total or partial (depending on the ratio between excipients) dissolution of the isotretinoin.
  • Different kinds of formulations (SEDDS® or suspensions) of isotretinoin have been formulated. For suspensions, it was possible to dissolve a high fraction of isotretinoin in the mix of excipients and even the whole quantity of the active ingredient if the manufacturing conditions (high temperature and long time of mixing) and the formulations were optimized.
  • Excipients particularly suitable for the dissolution of isotretinoin were lauroyl Macrogol-32 glycerides (Gelucire® 44/14, Gattefossé) and Stearoyl Macrogol-32 glycerides (Gelucire® 50/13, Gattefossé).
  • hydrophilic components When those hydrophilic components are melted together with an oily vehicle, it allows obtaining very stable suspensions of isotretinoin in which an important part of the active ingredient is dissolved.
  • a surfactant may also be added to the formulation to further improve the physical stability of the suspension.
  • SEDDS® formulations of isotretinoin are also stable and may give an improved bioavailability of the drug.
  • Ternary diagrams illustrate the different areas corresponding to different physical states, namely, coarse emulsion, true emulsion, lamellar solution or micellar solution, as the ratio between excipients is varied.
  • the behavior of the formulation in the presence of water changes when the ratio changes.
  • FIG. 1 One example of this ternary diagram is given in FIG. 1 for a formulation of isotretinoin containing Gelucire® 50/13 and soybean oil.
  • the effect of different lipophilic excipients was evaluated in the dosage form of semi-solid capsules.
  • the semi-solid capsules were made by addition of the active substance to the pre-melted lipophilic compounds followed by the filling of the liquid into hard gelatin capsule.
  • the active substance was incorporated into formulations, listed in table 1, consisting of glyceroyl macrogolglyceride associated with soybean oil or derivative, medium chain triglyceride.
  • stearoyl macroglyceride (Gelucire® 50/13, Gattefosse) and soybean oil allows provides a formulation with a dissolution profile similar to the reference (Roaccutane® 20 mg, Roche).
  • an oily excipient can improve the absorption of a lipophilic drug by increasing the solubility of the drug in the lipidic phase, but the release of the active ingredient from the formulation can be slowed down due to the high affinity of the lipophilic drug for the oily phase.
  • dispersed systems emulsions or suspensions
  • lipophilic or hydrophilic vehicles improves the absorption of the drug as well as increasing a larger contact surface.
  • Gelucire® the process of drug release varies according to the HLB of the excipient. Gelucire® with high HLB values were found to be the most favorable for a rapid release of the drug (by diffusion and erosion).
  • the percent of isotretinoin released from the reference (Roaccutane® 20 mg) after 4 hours is 55.37%.
  • Stearoyl macrogolglyceride (Gelucire® 50/13), which is known to be a drug solubilizer and emulsifying agent of different drugs (in SMEDDS® or SEDDS®), was tested in association with soybean oil.
  • This component has the ability to solubilize a great part of isotretinoin in the formulation. This data is listed in table III.
  • Formulations 1 and 2 formation of coarse emulsion with large droplet sizes
  • Formulations 4 and 6 formation of emulsion with homogeneous droplet size
  • the percentage of isotretinoin released increases generally with the percentage of Gelucire® in the formulation (increased solubility of the active in this vehicle).
  • For Formulation 3 ratio oil/Gelucire® 50/13: 0.2
  • the prediction power of the in vitro dissolution test is weak since the in vitro/in vivo correlation is known to be poor. Nevertheless, an optimized dissolution test (using enzymes and surfactant) is of some help to assess the rate of release of the drug from the lipidic composition. It must be noted that the conditions of the dissolution test (dissolution medium, speed of the paddles, temperature, etc.) influence the results of the test and should consequently be standardized to allow comparison between various formulations.
  • FIG. 2 shows the dissolution rate of a reference product (Roaccutane®—20 mg active agent), of a suspension containing 20 mg Isotretinoin and of an emulsion SEDDS® containing 10 mg Isotretinoin (formulation given below).
  • the caco-2 cell culture system can be used for determining permeability of compounds (especially for poorly soluble compounds).
  • the caco-2 cell model allows one to measure the transport of drug from the apical to the serosal side as well as from the serosal to the apical side. This gives the ability to determine if an efflux system is operational.
  • the caco-2 cells model is interesting because:
  • the formulations tested were put in solution in 250 ml of BME. Taurocholate (10 mM) was added to the solutions to better replicate the in vivo physiological conditions. The different solutions so prepared were put in contact with Caco-2 cells at the apical or basolateral side. The cells culture inserts were incubated for 3 hours at 37° C. and samples of 100 ⁇ l taken every hour for analysis.
  • FIG. 3 describes the mean pharmacokinetic profile obtained for each formulation.
  • suspension and SEDDS® formulations both presented a lower intra-individual variability of the bioavailability as demonstrated by the values of relative standard deviations (rsd) which are of 36.0%, 22.72% and 28.18% for Roaccutane® 20 mg, suspension 20 mg and SEDDS® 10 mg, respectively.
  • a second pharmacokinetic study was performed on completely different formulations (6 subjects, 2-way, fed, cross-over study). Specifically, in the second pharmacokinetic study the formulations of isotretinoin under the form of a suspension in which the ratio Gelucire® 50/13 and soybean oil was very different from the suspension formulation used in the first pharmacokinetic study.
  • FIG. 4 provides the comparative pharmacokinetic profiles of the isotretinoin formulations of Table VIII.
  • FIG. 5 provides the comparative pharmacokinetic profiles of the isotretinoin formulations of Table VIII for 4-oxo-isotretinoin, the active metabolite of isotretinoin.
  • the subjects were healthy Caucasian volunteers of both sexes (non-pregnant, non-breast-feeding), aged 18 to 50 years, non-smokers or smoking less than 10 cigarettes per day.
  • the drug was taken with food (a European breakfast).
  • Blood samples were collected according to the following sampling schedule: pre dose and 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 10 h, 12 h, 14 h, 24 h, 36 h, 48 h, 72 h, 96 h, 120 h, 168 h and 216 hours post-dose.
  • the dose of 16 mg of the formulation corresponding to the present invention gives a bioavailability similar to 20 mg of the marketed formulation, which provides evidence of the supra-bioavailability of the formulation corresponding to the present invention.
  • Table X and XI provide the value of the main pharmacokinetics results and statistical analysis obtained for each formulation (i.e., ROCCUTANE® 20 mg and isotretinoin 16 mg) of isotretinoin and 4-oxoisotretinoin.
  • Isotretinoin 16 mg according to the invention has a safety profile comparable to that described in the literature for other isotretinoin preparations and similar to that of ROACCUTANE®20 mg.
  • the pre-weighed amounts of stearyl macrogol glycerides, soybean oil, sorbitan monooleate, and propyl gallate were added in a double-jacketed stainless steel container equipped with a mixing device, and heated at a temperature between about 65° C. and about 85° C.
  • isotretinoin was added to the container while mixing.
  • 410 mg of the molten blend was added into size #0 gelatin capsules, producing capsules containing 20 mg of isotretinoin.
  • Dissolution testing A dissolution test using 6 capsules of the present example was performed. The dissolution test is performed in accordance with general rules of USP for dissolution testing
  • a dissolution medium pH 7.5 [20 L] was prepared by introducing 27.6 g of sodium dihydrogen phosphate in an appropriate container and dissolving it with about 4 liters of water. Next, 12 liters of water were added. Thereafter, 380 mL of sodium hydroxide 6N were progressively added under stirring. If needed, the mixture was sonicated until all of the sodium dihydrogen phosphate is dissolved. 940 g of cholic acid was progressively added under stirring until totally dispersed. If necessary, small amounts of NaOH 6N were added until dissolved. Water was added to bring the total volume to about 20 L, mixed, and the pH was adjusted to 7.5 with NaOH if necessary. The exact amount of medium to be used was then removed, and 1 g of pancreatin per each 900 mL of medium was added and mixed.
  • the dissolution test parameters were: dissolution volume 900 mL; temperature 37° C.; paddle rotation speed 100 rpm; test time for sampling 4 hours; quantification HPLC/UV at 353 nm ⁇ 4 nm.
  • the solution was immediately filtered slowly through a 0.45 ⁇ m filter, and the first milliliters were discarded and introduced into a glass vial.
  • the samples were further diluted by pipetting 5 mL of the sample and 5 mL of acetonitrile into a container.
  • the chromatographic conditions were: column LiCrospher® 100 RP-18 end capped (125 ⁇ 4 mm), 5 ⁇ m or equivalent; mobile phase acetonitrile:water:acetic acid glacial (85:15:0.5); flow rate 2.0 mL/min; temperature 40° C.; detection UV at A 353 nm ⁇ 4 nm; injection 80 ⁇ L; stop time 4 minutes.
  • Methylene Chloride Reagent One liter of methylene chloride was added to 50 g of sodium bicarbonate. The solution is shaken and allowed to stand overnight. At the time of use, it is filtered and 10 mg of butylated hydroxytoluene are added for each mL of reagent.
  • the objective of the study was to evaluate the comparative bioavailability between Isotretinoin 2 ⁇ 20 mg capsules (Example 1) and Accutane® 40 mg capsules in healthy male and female volunteers under fasting and fed conditions.
  • Treatment A Isotretinoin 20 mg Capsules [40 mg administered after an overnight fast of at least 10 hours]
  • Treatment B Isotretinoin 20 mg Capsules [40 mg administered after a modified high fat, high calorie breakfast]
  • Treatment C (Test): Accutane® 40 mg Capsules, Lot No.: U0622; [40 mg administered after an overnight fast of at least 10 hours]
  • Treatment D (Test): Accutane® 40 mg Capsules, Lot No.: U0622; Expiration Date: 10-2004 [40 mg administered after a modified high fat, high calorie breakfast]
  • Blood samples were obtained at ⁇ 10, ⁇ 2, 0, 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 10, 12, 14, 16, 20, 24, 36, 48, and 72 hours following drug administration.
  • USP United States Pharmacopeia
  • a small aliquot of sample is taken from each vessel, usually by a multi channeled pumping system, and transported to either a cuvette or a sample vial for subsequent spectrophotometric or high pressure liquid chromatography (HPLC) analysis, respectively. Plotting percentage dissolution of a solid dosage form through time results in a dissolution profile.
  • Absorica® see composition in Table XII
  • Claravis® and/or Amnesteen® which are both products with food effect.
  • the dissolution method USP #1 uses the disintegration equipment.
  • This is a 2 tier method which comprises a 30 minute capsule soaking in a simulated gastric fluid with pepsin followed by a 60 minute disintegration period in a medium brought to pH 10 with the addition of NaOH 0.13N.
  • the isotretinoin concentration as a function of time is measured by spectroscopy UV at 343 nm.
  • the specification is NLT 80% (Q) at 90 minutes.
  • the dissolution method USP #2 is carried out at pH 7.8 buffer containing 0.5% w/v of surfactant N,N-Dimethyldodecylamine N-oxide using USP apparatus #1 (basket) at a speed of 100 rpm and a temperature of 37° C.
  • the duration of the test is 90 minutes and the specification is NLT 80% (Q) at 90 minutes. Samples are analyzed by HPLC. Upon completion of the test after 90 minutes the following observations were made:
  • the dissolution method USP #3 uses borate buffer at pH 8.0, cetrimide and pancreatin.
  • the test is performed using USP apparatus #2 (paddles) at 75 rpm.
  • the isotretinoin is determined by HPLC and the test is successful if after 90 min 70% (Q) is released.
  • This method is able to dissolve the isotretinoin of the Absorica® capsules within the specified time but is not able to distinguish between isotretinoin containing capsules with food effect (Claravis®) and without food effect (Absorica®).
  • Dissolution tests were performed on Absorica® capsules (on isotretinoin-containing capsules without food effect) using dissolution media simulating gastro intestinal fasted and fed states.
  • This study used the dissolution media as indicated in Margareth Marque's article: “Dissolution Media Simulating Fasted and Fed States” as appears in Dissolution Technologies May 2004 Volume 11 Issue 2. The contents of this article are incorporated herein in their entirety for its teaching of dissolution media and their preparation and use.
  • This media has a pH of 6.50 and an osmolality of about 270 mOsmol/kg.
  • This media has a pH of 5.00 and an osmolality of about 670 mOsmol/kg.
  • Isotretinoin 40 mg Absorica® capsules were carried out in 500 mL of FaSSIF media and in 1000 mL of FeSSIF media using the USP Apparatus #2 (Paddles), at 100 rpm and 37° C. Dissolution samples were taken after 1 and 2 hours, and diluted to 50% with Acetonitrile. 90 ⁇ L were injected into an HPLC equipped with a UV detector at 353 nm, using a 5 ⁇ m 12.0 cm ⁇ 4 mm C18 Column (like Lichrocart 100RP-18 endcapped or equivalent). The flow rate was 2.0 mL/min of mobile phase consisting of Acetonitrile:Water:Glacial Acetic Acid (85:15:0.5) at a temperature of 40° C. The samples were compared to an isotretinoin standard solution of known concentration.
  • the fasted simulating media (FaSSIF) only dissolves 15% of Absorica® 40 mg capsules after 2 hours.
  • the Fed simulating media (FeSSIF) only dissolve 18% of Absorica® 40 mg capsules after 2 hours.
  • Example 3 The use of the dissolution method of Example 3 is of great importance for the optimization of dosing conditions and product formulation since it can differentiate between isotretinoin formulations with or without significant food effect.
  • biorelevant dissolution test could be used to assess bioequivalence of post-approval formulation changes in drug product form.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Dermatology (AREA)
  • Zoology (AREA)
  • Botany (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
US14/133,073 2012-06-18 2013-12-18 Pharmaceutical semi-solid composition of isotretinoin Active US9078925B2 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
US14/133,073 US9078925B2 (en) 2012-06-18 2013-12-18 Pharmaceutical semi-solid composition of isotretinoin
EP14872811.6A EP2964195A4 (fr) 2013-12-18 2014-11-21 Composition semi-solide pharmaceutique d'isotrétinoïne
PCT/US2014/066756 WO2015094574A1 (fr) 2013-12-18 2014-11-21 Composition semi-solide pharmaceutique d'isotrétinoïne

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US13/525,857 US8952064B2 (en) 2000-09-22 2012-06-18 Pharmaceutical semi-solid composition of isotretinoin
US13/525,904 US20130096196A1 (en) 2000-09-22 2012-06-18 Pharmaceutical semi-solid composition of isotretinoin
US13/713,897 US9089534B2 (en) 2000-09-22 2012-12-13 Pharmaceutical semi-solid composition of isotretinoin
US14/133,073 US9078925B2 (en) 2012-06-18 2013-12-18 Pharmaceutical semi-solid composition of isotretinoin

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US13/713,897 Continuation-In-Part US9089534B2 (en) 2000-09-22 2012-12-13 Pharmaceutical semi-solid composition of isotretinoin

Publications (2)

Publication Number Publication Date
US20140107203A1 US20140107203A1 (en) 2014-04-17
US9078925B2 true US9078925B2 (en) 2015-07-14

Family

ID=50475895

Family Applications (1)

Application Number Title Priority Date Filing Date
US14/133,073 Active US9078925B2 (en) 2012-06-18 2013-12-18 Pharmaceutical semi-solid composition of isotretinoin

Country Status (3)

Country Link
US (1) US9078925B2 (fr)
EP (1) EP2964195A4 (fr)
WO (1) WO2015094574A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10517846B2 (en) 2016-05-26 2019-12-31 Dr. Reddy's Laboratories Ltd. Pharmaceutical compositions for treating acne
US10716774B1 (en) 2018-01-05 2020-07-21 Yale Pharmaceuticals LLC Pharmaceutical compositions containing isotretinoin with improved dissolution profile and enhanced stability
US10813880B2 (en) 2017-06-29 2020-10-27 Skyline Biosciences Llc Isotretinoin oral-mucosal formulations and methods for using same

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MX2016015465A (es) * 2014-05-29 2017-03-27 Sun Pharmaceutical Ind Ltd Composicion farmaceutica oral de isotretinoina.
BR112017001963A2 (pt) 2014-07-31 2017-11-21 Sun Pharmaceutical Ind Ltd composição farmacêutica oral, seu processo de preparação e método de tratamento
US9750711B2 (en) * 2014-10-01 2017-09-05 Sun Pharmaceutical Industries Limited Low dose oral pharmaceutical composition of isotretinoin
MA40781A (fr) * 2014-10-01 2017-08-08 Sun Pharmaceutical Ind Ltd Composition pharmaceutique d'isotrétinoïne à faible dosage destinée à la voie orale

Citations (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4464394A (en) 1970-06-23 1984-08-07 Hoffmann Laroche Inc. Compositions and methods for using 13-cis vitamin A acid compounds
WO1985003434A1 (fr) 1984-02-06 1985-08-15 Neutrogena Corporation Vehicule ameliore d'administration d'ingredients pharmaceutiques actifs sur la peau humaine
EP0184942A2 (fr) 1984-12-14 1986-06-18 Ortho Pharmaceutical Corporation Compositions pharmaceutiques contenant de l'acide 13-Cis vitaminique A comme ingrédient actif
US5185264A (en) 1990-11-09 1993-02-09 Abbott Laboratories Diluent buffer and method for diluting an assay component
US5252604A (en) 1992-07-10 1993-10-12 Hoffmann-La Roche Inc. Compositions of retinoic acids and tocopherol for prevention of dermatitis
US5993858A (en) 1996-06-14 1999-11-30 Port Systems L.L.C. Method and formulation for increasing the bioavailability of poorly water-soluble drugs
WO2000000179A1 (fr) 1998-06-27 2000-01-06 Won Jin Biopharma Co., Ltd. Preparation a dispersion solide d'un medicament faiblement hydrosoluble contenant de l'huile, un acide gras ou leurs melanges
US6020003A (en) 1998-02-23 2000-02-01 Basf Corporation Method of making spray-dried powders with high edible-oil loadings based on non-hydrolyzed gelatin
US6054136A (en) 1993-09-30 2000-04-25 Gattefosse S.A. Orally administrable composition capable of providing enhanced bioavailability when ingested
WO2000025772A1 (fr) 1998-10-30 2000-05-11 F. Hoffmann-La Roche Ag Compositions d'isotretinoine de faible granulometrie et procede de production associe
US6248363B1 (en) 1999-11-23 2001-06-19 Lipocine, Inc. Solid carriers for improved delivery of active ingredients in pharmaceutical compositions
US6267985B1 (en) 1999-06-30 2001-07-31 Lipocine Inc. Clear oil-containing pharmaceutical compositions
US6294192B1 (en) 1999-02-26 2001-09-25 Lipocine, Inc. Triglyceride-free compositions and methods for improved delivery of hydrophobic therapeutic agents
US20020025338A1 (en) 2000-06-16 2002-02-28 Abha Pant Bioavailable dosage form of isotrentinoin
CA2423170A1 (fr) 2000-09-22 2002-03-28 Galephar M/F Composition pharmaceutique semi-solide d'isotretinoine
US6383471B1 (en) 1999-04-06 2002-05-07 Lipocine, Inc. Compositions and methods for improved delivery of ionizable hydrophobic therapeutic agents
US20030077297A1 (en) 1999-02-26 2003-04-24 Feng-Jing Chen Pharmaceutical formulations and systems for improved absorption and multistage release of active agents
US6593292B1 (en) 1999-08-24 2003-07-15 Cellgate, Inc. Compositions and methods for enhancing drug delivery across and into epithelial tissues
US6624154B1 (en) 1999-04-23 2003-09-23 Bristol-Myers Squibb Company Compositions and methods for treatment of hyperproliferative diseases
US20070026062A1 (en) 2003-10-10 2007-02-01 Lifecycle Pharma A/S Tablet comprising a fibrate
RU2400226C1 (ru) 2009-06-08 2010-09-27 Юрий Степанович Макляков Способ лечения угревой болезни
CA2762391A1 (fr) 2009-05-20 2010-11-25 Ranbaxy Laboratories Limited Formes posologiques liquides d'isotretinoine
US20130189318A1 (en) * 2003-08-29 2013-07-25 Veloxis Pharmaceuticals A/S Solid dispersions comprising tacrolimus

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4545977A (en) 1985-01-11 1985-10-08 G. D. Searle & Co. Compositions and methods for treating severe acne with isotretinoin
US5567592A (en) 1994-02-02 1996-10-22 Regents Of The University Of California Screening method for the identification of bioenhancers through the inhibition of P-glycoprotein transport in the gut of a mammal
US5716928A (en) 1995-06-07 1998-02-10 Avmax, Inc. Use of essential oils to increase bioavailability of oral pharmaceutical compounds
SE0303135D0 (sv) * 2003-11-25 2003-11-25 Lipocore Holding Ab Controlled food effect composition

Patent Citations (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4464394A (en) 1970-06-23 1984-08-07 Hoffmann Laroche Inc. Compositions and methods for using 13-cis vitamin A acid compounds
WO1985003434A1 (fr) 1984-02-06 1985-08-15 Neutrogena Corporation Vehicule ameliore d'administration d'ingredients pharmaceutiques actifs sur la peau humaine
EP0184942A2 (fr) 1984-12-14 1986-06-18 Ortho Pharmaceutical Corporation Compositions pharmaceutiques contenant de l'acide 13-Cis vitaminique A comme ingrédient actif
US5185264A (en) 1990-11-09 1993-02-09 Abbott Laboratories Diluent buffer and method for diluting an assay component
US5252604A (en) 1992-07-10 1993-10-12 Hoffmann-La Roche Inc. Compositions of retinoic acids and tocopherol for prevention of dermatitis
US6054136A (en) 1993-09-30 2000-04-25 Gattefosse S.A. Orally administrable composition capable of providing enhanced bioavailability when ingested
US5993858A (en) 1996-06-14 1999-11-30 Port Systems L.L.C. Method and formulation for increasing the bioavailability of poorly water-soluble drugs
US6020003A (en) 1998-02-23 2000-02-01 Basf Corporation Method of making spray-dried powders with high edible-oil loadings based on non-hydrolyzed gelatin
WO2000000179A1 (fr) 1998-06-27 2000-01-06 Won Jin Biopharma Co., Ltd. Preparation a dispersion solide d'un medicament faiblement hydrosoluble contenant de l'huile, un acide gras ou leurs melanges
WO2000025772A1 (fr) 1998-10-30 2000-05-11 F. Hoffmann-La Roche Ag Compositions d'isotretinoine de faible granulometrie et procede de production associe
US6294192B1 (en) 1999-02-26 2001-09-25 Lipocine, Inc. Triglyceride-free compositions and methods for improved delivery of hydrophobic therapeutic agents
US20030077297A1 (en) 1999-02-26 2003-04-24 Feng-Jing Chen Pharmaceutical formulations and systems for improved absorption and multistage release of active agents
US6383471B1 (en) 1999-04-06 2002-05-07 Lipocine, Inc. Compositions and methods for improved delivery of ionizable hydrophobic therapeutic agents
US6624154B1 (en) 1999-04-23 2003-09-23 Bristol-Myers Squibb Company Compositions and methods for treatment of hyperproliferative diseases
US6267985B1 (en) 1999-06-30 2001-07-31 Lipocine Inc. Clear oil-containing pharmaceutical compositions
US6593292B1 (en) 1999-08-24 2003-07-15 Cellgate, Inc. Compositions and methods for enhancing drug delivery across and into epithelial tissues
US6923988B2 (en) 1999-11-23 2005-08-02 Lipocine, Inc. Solid carriers for improved delivery of active ingredients in pharmaceutical compositions
US6248363B1 (en) 1999-11-23 2001-06-19 Lipocine, Inc. Solid carriers for improved delivery of active ingredients in pharmaceutical compositions
US20020025338A1 (en) 2000-06-16 2002-02-28 Abha Pant Bioavailable dosage form of isotrentinoin
CA2423170A1 (fr) 2000-09-22 2002-03-28 Galephar M/F Composition pharmaceutique semi-solide d'isotretinoine
US20040009225A1 (en) 2000-09-22 2004-01-15 Francis Vanderbist Pharmaceutical semi-solid composition of isotretinoin
US20130217769A1 (en) 2000-09-22 2013-08-22 Galephar Pharmaceutical Research, Inc. Pharmaceutical semi-solid composition of isotretinoin
US20130189318A1 (en) * 2003-08-29 2013-07-25 Veloxis Pharmaceuticals A/S Solid dispersions comprising tacrolimus
US20070026062A1 (en) 2003-10-10 2007-02-01 Lifecycle Pharma A/S Tablet comprising a fibrate
CA2762391A1 (fr) 2009-05-20 2010-11-25 Ranbaxy Laboratories Limited Formes posologiques liquides d'isotretinoine
RU2400226C1 (ru) 2009-06-08 2010-09-27 Юрий Степанович Макляков Способ лечения угревой болезни

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
"Effect of Lipid Vehicle on the intestinal lymphatic transport of isotretinoin in the rat", International Journal of Pharmaceutics, 119:173-181 (1995).
Constantinides, "Lipid microemulsions for improving drug dissolution and oral absorption: Physical and Biopharmaceutical Aspects", Pharmaceutical Resarch, vol. 12 No. 11 (1995).
Gershanik, "Self-dispersing lipid formulations for improving oral absorption of lipophilic drugs", Eur. Journal of Pharmaceuticals & Biopharm., 50:179-188 (2000).
International Journal of Pharmaceutics, 106:15-23 (1994), "Self-emulsifying drug delivery systems (SEDDS) with Polyglycolized Glycerides for improving in vitro dissolution and oral absorption of lipophilic drugs".
Koga, K. et al. "In vitro and in situ evidence for the contribution of Labrasol and Gelucire 44/14 on transport of cephalexin and cefoperazone by rat intestine", Eur. J. Pharm. Biopharm. Nov. 2002 54(3): 311-8.
Koga, K., et al. "In vitro and in situ evidence for the contribution of Labrosol and Gelucire 44/14 on transport of cephalexin and cefoperazone by rat interstine", Eur. J. Pharm. Biopharm., Nov. 2002 54(3):311-8.
Nankervis, et al. "Intestinal lymphotic transport of three retinoids in the rat after oral administration:effect of lipophilicity and lipid vehicle", International Journal of Pharmaceutics, 130:57-64 (1996).

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10517846B2 (en) 2016-05-26 2019-12-31 Dr. Reddy's Laboratories Ltd. Pharmaceutical compositions for treating acne
US10813880B2 (en) 2017-06-29 2020-10-27 Skyline Biosciences Llc Isotretinoin oral-mucosal formulations and methods for using same
US10874607B2 (en) 2017-06-29 2020-12-29 Skyline Biosciences Llc Isotretinoin oral-mucosal formulations and methods for using same
US10716774B1 (en) 2018-01-05 2020-07-21 Yale Pharmaceuticals LLC Pharmaceutical compositions containing isotretinoin with improved dissolution profile and enhanced stability

Also Published As

Publication number Publication date
WO2015094574A1 (fr) 2015-06-25
US20140107203A1 (en) 2014-04-17
EP2964195A1 (fr) 2016-01-13
EP2964195A4 (fr) 2016-09-21

Similar Documents

Publication Publication Date Title
US9089534B2 (en) Pharmaceutical semi-solid composition of isotretinoin
US9078925B2 (en) Pharmaceutical semi-solid composition of isotretinoin
Perlman et al. Development of a self-emulsifying formulation that reduces the food effect for torcetrapib
EP3735230B1 (fr) Composition à libération modifiée contenant un cannabinoïde
Setthacheewakul et al. Development and evaluation of self-microemulsifying liquid and pellet formulations of curcumin, and absorption studies in rats
Xue et al. Preparation and optimization of rivaroxaban by self-nanoemulsifying drug delivery system (SNEDDS) for enhanced oral bioavailability and no food effect
Araya et al. The novel formulation design of O/W microemulsion for improving the gastrointestinal absorption of poorly water soluble compounds
Morakul Self-nanoemulsifying drug delivery systems (SNEDDS): an advancement technology for oral drug delivery
Hu et al. Sirolimus solid self-microemulsifying pellets: formulation development, characterization and bioavailability evaluation
Woo et al. Reduced food-effect and enhanced bioavailability of a self-microemulsifying formulation of itraconazole in healthy volunteers
EP2062571B1 (fr) Composition pharmaceutique à auto-émulsion avec une biodisponibilité améliorée
Pattewar et al. Self microemulsifying drug delivery system: A lipid based drug delivery system
Li et al. Formulation, biological and pharmacokinetic studies of sucrose ester-stabilized nanosuspensions of oleanolic acid
Chudasama et al. Role of lipid-based excipients and their composition on the bioavailability of antiretroviral self-emulsifying formulations
Taha et al. Bioavailability assessment of vitamin A self-nanoemulsified drug delivery systems in rats: a comparative study
Park et al. In vitro and in vivo comparative study of itraconazole bioavailability when formulated in highly soluble self‐emulsifying system and in solid dispersion
Goyal et al. Self microemulsifying drug delivery system: A method for enhancement of bioavailability
WO2019053581A1 (fr) Composition pharmaceutique
CA2836228A1 (fr) Composition pharmaceutique semi-solide d'isotretinoine
Reddy et al. Review on self micro emulsifying drug delivery systems
TW202128150A (zh) ３＇—［（２ｚ）—［１—（３，４—二甲基苯基）—１，５—二氫—３—甲基—５—側氧基—４ｈ—吡唑—４—亞基］肼基］—２＇—羥基—［１，１＇—聯苯基］—３—甲酸及其鹽配製物
Baratam et al. a Promising Approach To Enhance Solubility and Bioavailability By Self Emulsifying Drug Delivery System: a Brief Review
Dutta et al. Design, Optimization and Pharmacokinetic Profiling of BCS Class II Drug Loaded Oral Self Nanoemulsifying System
Klein In vitro lipolysis assay as a prognostic tool for the development of lipid based drug delivery systems
Buch Solubility and permeability as in vitro predictors for in vivo performance of fenofibrate IR solid dosage forms

Legal Events

Date Code Title Description
AS Assignment

Owner name: GALEPHAR PHARMACEUTICAL RESEARCH, INC., PUERTO RIC

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:DEBOECK, ARTHUR;VANDERBIST, FRANCIS;SERVAIS, CECILE;AND OTHERS;SIGNING DATES FROM 20150310 TO 20150319;REEL/FRAME:035208/0032

STCF Information on status: patent grant

Free format text: PATENTED CASE

MAFP Maintenance fee payment

Free format text: PAYMENT OF MAINTENANCE FEE, 4TH YEAR, LARGE ENTITY (ORIGINAL EVENT CODE: M1551)

Year of fee payment: 4

MAFP Maintenance fee payment

Free format text: PAYMENT OF MAINTENANCE FEE, 8TH YEAR, LARGE ENTITY (ORIGINAL EVENT CODE: M1552); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

Year of fee payment: 8